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Evaluating the Roles of Follicle-Stimulating Hormone Receptor Polymorphisms in Gonadal Hyperstimulation Associated with Severe Juvenile Primary Hypothyroidism

Division of Reproductive Endocrinology and Infertility (G.L.R., B.J.V.V.), and Department of Molecular Physiology and Biophysics (X.F., M.Z., D.L.S.), University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa 52242; Developmental Endocrinology Unit and Laboratory of Hormone and Genetic Molecular LIM/42 (C.B.d., E.M.P., A.C.L.), Sao Paulo University Medical School, Sao Paulo 05403-900, Brazil; and Division of Pediatric Endocrinology, Department of Pediatrics (A.E.F.K., S.R.A.), School of Medicine of Ribeirão Preto, University of Sao Paulo, Sao Paulo 1409-900, Brazil

Address all correspondence and requests for reprints to: Deborah L. Segaloff, Ph.D., Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52246. E-mail: deborah-segaloff{at}uiowa.edu.

Context: Rare activating mutations of the human (h)FSHR have been reported in some women with spontaneous ovarian hyperstimulation in pregnancy, where follicular growth is inappropriately stimulated by elevated concentrations of human chorionic gonadotropin acting through the hFSHR. It is not known whether ovarian hyperstimulation in peripubertal girls with untreated primary hypothyroidism is caused by hFSHR mutations and/or influenced by hFSHR allelic variants, rendering the hFSHR more sensitive to circulating TSH.

Objective: The aim of the study was to determine whether mutations of the hFSHR and/or hFSHR allelic variants are associated with greater sensitivity of the hFSHR to TSH.

Design: The hFSHR gene was sequenced from eight pediatric patients displaying gonadal hyperstimulation due to primary hypothyroidism. HEK293 cells expressing different hFSHR allelic combinations were studied for their responsiveness to recombinant (r)hTSH.

Setting: The study was conducted at university research centers.

Patients: Eight unrelated patients (seven girls and one boy) who exhibited primary hypothyroidism and gonadal hyperstimulation were included in the study.

Interventions: There were no interventions.

Main Outcome Measure: DNA sequencing of the hFSHR gene was the main outcome measure. Basal, rhFSHR- and rhTSH receptor-stimulated cAMP levels were assayed in HEK293 cells transfected with the hTSH receptor or different hFSHR allelic combinations. Cell surface receptor numbers were also determined.

Results: No hFSHR mutations were identified in the patient population, but we did identify two known polymorphisms. In vitro experiments demonstrated a dose-dependent and specific rhTSH-dependent increase in cAMP production in HEK293 cells expressing the wild-type hFSHR, regardless of hFSHR isoform.

Conclusions: Pediatric gonadal hyperstimulation associated with severe primary hypothyroidism is likely due to the actions of the elevated concentrations of TSH on the wild-type hFSHR, and this response is not dependent upon the hFSHR isoform.

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